Nitric oxide (NO) is a highly reactive free radical compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3′,5′-monophosphate (cGMP), leading to vasodilation.
When inhaled, NO gas acts as a selective vasodilator of human and animal pulmonary vessels. Consequently, NO inhalation is used to promote vasodilation in well-ventilated regions of the lung. In acute respiratory distress syndrome (ARDS), impaired ventilation of lung tissue reduces oxygenation of arterial blood. Nitric oxide inhalation often improves oxygenation in ARDS patients. It does so by dilating blood vessels in well-ventilated portions of the lung, redistributing blood flow towards the well-ventilated regions and away from poorly-ventilated regions, which receive little NO. However, in 30-40% of ARDS patients, NO inhalation fails to improve arterial oxygenation (Bigatello et al., 1994, Anesthesiology 80:761-770; Dellinger et al., 1998, Crit. Care Med. 26:15-23). It is difficult to predict which patients with ARDS will not respond to NO inhalation or which patients will respond only transiently. However, it is known that up to 60% of patients with ARDS associated with sepsis do not respond to inhaled NO (Krafft et al., 1996, Chest 109:486-493).
Normal pulmonary vasculature constricts in response to alveolar hypoxia. In patients with lung injury such as ARDS, hypoxic pulmonary vasoconstriction (HPV) raises the level of systemic arterial oxygenation by redistributing blood flow away from a poorly ventilated (hypoxic) lung or lung region toward a well-ventilated (normoxic) lung regions. Sepsis and endotoxemia impair HPV (Hutchinson et al., 1985, J. Appl. Physiol. 58:1463-1468) leading to a profound decrease in arterial oxygen concentrations. Such a decreased level of systemic oxygenation can be life-threatening. Nitric oxide inhalation might be expected to improve oxygenation or arterial blood during sepsis, by increasing blood flow in well-ventilated regions on the lung. In practice, however, NO inhalation during sepsis is often ineffective, and sometimes is deleterious, because of NO inhalation-related reduction of HPV. See, e.g., Gerlach et al., 1996, “Low levels of inhaled nitric oxide in acute lung injury,” pages 271-283 in Nitric Oxide and the Lung, (Zapol and Bloch, eds.), Marcel Dekker Inc, New York.
Endogenous NO is produced by nitric oxide synthases through conversion of L-arginine to L-citrulline in the presence of oxygen (Knowles et al., 1994, Biochemistry 298:249-258). Three different forms of nitric oxide synthase (NOS) have been characterized. Neuronal NOS (NOS1) and endothelial NOS (NOS3) are constitutive enzymes. An inducible NOS known as NOS2 capable of producing large amounts of NO is induced by endotoxin (also referred to as lipopolysaccharide or LPS) and cytokines (Knowles et al., supra). In spite of the demonstrated value of NO inhalation therapy for various indications, impaired pulmonary vascular dilatory responsiveness to NO inhalation and NO-related loss of HPV remain significant problems in acute respiratory illness.